Metabolic dysfunction-associated steatotic liver disease (MASLD) is a chronic liver disease characterized by liver fat accumulation and combined with metabolic dysfunction (such as obesity, type 2 diabetes, dyslipidemia, etc.) [
1]. Its core mechanism is closely related to insulin resistance, lipid metabolism disorders, and chronic inflammation. If MASLD is not controlled, it can develop into liver fibrosis, cirrhosis, and even increase the risk of HCC in severe cases [
2]. MASLD is a global disease, and treating it is also a challenge for all of us.
In the study by Ciociola et al. [
3] published in this issue of
Clinical and Molecular Hepatology, their finding is that the
MARC1 rs2642438 minor allele encoding the p.T165 variant results in lower hepatocyte triglyceride content by increasing β-oxidation in PHHs. Moreover, the downregulation of
MARC1 p.A165 results in a more favourable phenotype by reducing ferroptosis and ROS levels. This is a very interesting study, however, there are several aspects that require further clarification and enhancement.
The authors only used one risk allele (MARC1 p.A165) and one protective allele (MARC1 p.T165) from one donor as the source of primary liver cells (PHH), without specifying the donor's metabolic background (such as BMI, insulin sensitivity, etc.). If the author could include 3–5 different donors and stratify the impact of metabolic phenotype, it would be more perfect. The main experiment in the article focuses on the MARC1 p.A165 risk allele, but MARC1 p.T165 (protective type) shows no phenotypic changes after knockdown. Why further knocking down MARC1 p.T165 has no effect when it has decreased by 50%, and whether there may be a compensation mechanism or threshold effect; Does MARC1 p.T165 regulate fatty acid metabolism through non MARC1 pathways (such as FXR/PGC-1α).
The authors used hepatocellular carcinoma cell line (HepG2) as a substitute cell line for experiments and found that the lipid metabolism pathway of HCC cells was abnormal. In high-fat diet (HFD) induced HCC or steatohepatitis HCC, the fatty acid oxidation pathway was often downregulated to protect HCC cells from fat toxicity (low beta oxidation ability). However, the basal metabolic rates and lipid metabolism levels are different between normal liver cells/adipocytes and HCC cells [
4].
It is necessary for the authors to use ³H-palmitic acid to determine the overall β-oxidation level in the article. We all know that fatty acids undergo complete oxidation and incomplete oxidation during metabolism [
5]. The product of complete oxidation is CO
2, while the product of incomplete oxidation contains acid soluble metabolites (such as β-hydroxybutyric acid, acetoacetic acid and acetone). These products may have an impact on the experimental results [
6], therefore, we suggest that the experiment of generating
14CO
2 from
14C-palmitic acid can be supplemented to make it more convincing. Additionally, as an important factor, fatty acid beta oxidation can increase mitochondrial membrane permeability, enhance mitochondrial respiratory activity, lead to proton leakage, promote fatty acid degradation, but also increase ROS generation [
7], but this study showed a decrease in ROS (Fig. 5A).
In all, we greatly appreciate the groundbreaking work of Ciociola and the team. This is a very interesting research paper, from which we have learned a lot about MARC1 p.A165.
FOOTNOTES
-
Authors’ contributions
XJ and SG collected the literature. XJ, SG, ST and LJD finally approved the publication, XJ wrote the manuscript. XJ, SG and ST contributed equally. All authors read and approved the final manuscript.
-
Acknowledgements
Supported by Sichuan Natural Science Foundation (2024NSFSC1933, 2024NSFSC1896), Bureau of Science and Technology Nanchong City (23JCYJPT0065, 23JCYJPT0069, 23JCYJPT0071, 23JCYJPT0031), Research Project of Sichuan Medical Association (S23033), Outstanding Youth Fund Project of North Sichuan Medical College (CBY23-JQ02).
-
Conflicts of Interest
The authors declare no conflict of interest.
Abbreviations
metabolic dysfunction-associated steatotic liver disease
primary human hepatocytes
REFERENCES
- 1. Gofton C, Upendran Y, Zheng MH, George J. MAFLD: How is it different from NAFLD? Clin Mol Hepatol 2023;29(Suppl):S17-S31.
- 2. Vitale A, Svegliati-Baroni G, Ortolani A, Cucco M, Dalla Riva GV, Giannini EG, et al. Epidemiological trends and trajectories of MAFLD-associated hepatocellular carcinoma 2002-2033: the ITA.LI.CA database. Gut 2023;72:141-152.
- 3. Ciociola E, Dutta T, Sasidharan K, Kovooru L, Noto FR, Pennisi G, et al. Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-oxidation. Clin Mol Hepatol 2025;31:445-459.
- 4. Hansson PK, Asztély AK, Clapham JC, Schreyer SA. Glucose and fatty acid metabolism in McA-RH7777 hepatoma cells vs. rat primary hepatocytes: responsiveness to nutrient availability. Biochim Biophys Acta 2004;1684:54-62.
- 5. Liao J, Xie X, Wang N, Wang Y, Zhao J, Chen F, et al. Formononetin promotes fatty acid β-oxidation to treat non-alcoholic steatohepatitis through SIRT1/PGC-1α/PPARα pathway. Phytomedicine 2024;124:155285.
- 6. Lockman KA, Baren JP, Pemberton CJ, Baghdadi H, Burgess KE, Plevris-Papaioannou N, et al. Oxidative stress rather than triglyceride accumulation is a determinant of mitochondrial dysfunction in in vitro models of hepatic cellular steatosis. Liver Int 2012;32:1079-1092.
- 7. Karkucinska-Wieckowska A, Simoes ICM, Kalinowski P, Lebiedzinska-Arciszewska M, Zieniewicz K, Milkiewicz P, et al. Mitochondria, oxidative stress and nonalcoholic fatty liver disease: A complex relationship. Eur J Clin Invest 2022;52:e13622.
Citations
Citations to this article as recorded by
- Correspondence to editorial on “Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-oxidation”
Ester Ciociola, Tanmoy Dutta, Rosellina M. Mancina, Stefano Romeo
Clinical and Molecular Hepatology.2026; 32(2): e216. CrossRef - Metabolic dysfunction-associated steatotic liver disease: On track to become the dominant etiology of hepatocellular carcinoma: Reply to correspondence on “Downregulation of the MARC1 p.A165 risk allele reduces hepatocyte lipid content by increasing beta-
Jian Xu, Wei Zhang, Guo Wu, Jingdong Li
Clinical and Molecular Hepatology.2026; 32(2): e257. CrossRef
